The etiology of Alzheimer's disease (AD) is highly complex, and both genetic and environmental factors have been implicated. Olfactory deficits have long been known to precede clinical signs of dementia, and olfactory structures show similar signs of pathology as those in the CNS. However, why the olfactory system is particularly susceptible is not known. Here we provide a novel model to study neurodegeneration in AD within the olfactory system. We demonstrate that the Notch2 receptor plays a key role in maintaining normal glial function in the olfactory epithelium. In the absence of Notch2, glial function is progressively compromised, ultimately leading to neurodegeneration in adult animals. Glia serve many roles in supporting neuronal survival, including ameliorating and potentially exacerbating oxidative stress. A central hypothesis in AD is the role of oxidative stress upon neurodegeneration. We will study the effects of Notch2 upon regulation of glial response to oxidative stress in vivo and in vitro. Understanding how altered Notch2 signaling leads to neurodegeneration has important implications for understanding how neuronal survival is affected in AD. PUBLIC HEALTH RELEVANCE: This project aims to provide insight into how neurodegeneration develops in Alzheimer's disease. We focus specifically on the olfactory system, and use a molecular genetic approach towards dissecting the role of the Notch pathway in degeneration.